Age-related thymic involution contributes to age-associated immunodeficiency, increasing morbidity and mortality in the elderly. Thymic involution results in a reduced capacity to generate a robust, self-tolerant T cell population. As the thymus ages, changes in proliferation, differentiation, and apoptosis in the thymic stroma disorganize the cellular microenvironments that support this process. The number, diversity, and self-tolerance of T cells exiting the thymus are greatly reduced. The aging thymic stroma contains increasing numbers of adipocytes, resulting, in part, in increasing concentrations of inflammatory cytokines. Ultimately, the peripheral T cell population becomes less diverse, crippling adaptive immunity, and potentially more auto-reactive, increasing autoimmunity. Defining the molecular character of the young thymus and delineating the gene regulatory networks governing homeostasis and involution may help determine how this process may be avoided, delayed, or altered. We have identified the Activating Transcription Factor 3 gene (Atf3) as a potential regulator of some of the characteristic hallmarks of age-related thymic involution. ATF3 is a hub of the inflammatory response and induction by stress mediates cell survival, apoptosis, or differentiation, depending upon the cell type and stimulus driving expression. Our initial analysis of the Atf3 null mutant showed decreased involution phenotypes compared to age-matched controls as late as 1.5 years. Our preliminary data show that Atf3 may act downstream of the transcription factor FOXN1, a key regulator of thymic organogenesis and postnatal homeostasis that has been strongly implicated as a driving force in regulating thymic involution. Atf3-/- single mutants also have increased adipocity in the thymus, suggesting that ATF3 may suppress this aspect of aging-related involution. Based on these data and on its roles in other tissues, Atf3 may represent a molecular target of the stress response directly contributing to age-related thymic involution. Our hypothesis is that ATF3 depletes TECs from the thymic stroma by promoting apoptosis and epithelial to mesenchymal transition (EMT), but limits adipocyte accumulation in the degenerating thymus by repressing adipogenesis. We propose three specific aims designed to identify the specific roles and cellular targets for ATF3 function during aging-associated thymic involution.